CN1512892A - 口服施用甲状旁腺激素和降钙素 - Google Patents
口服施用甲状旁腺激素和降钙素 Download PDFInfo
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- CN1512892A CN1512892A CNA028111613A CN02811161A CN1512892A CN 1512892 A CN1512892 A CN 1512892A CN A028111613 A CNA028111613 A CN A028111613A CN 02811161 A CN02811161 A CN 02811161A CN 1512892 A CN1512892 A CN 1512892A
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- calcitonin
- effective amount
- oral administration
- orally administering
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明涉及口服施用甲状旁腺激素(PTH)的方法，其包括向需要PTH的患者口服联合施用有效量的PTH和有效量的降钙素。本发明的方法允许口服施用PTH并且没有高血钙症、高血尿症和肾结石的副作用。
Description
发明背景
1.发明领域
本发明涉及口服施用甲状旁腺激素(PTH)。更特别地，本发明涉及降钙素与PTH联合、用于口服施用PTH的用途。
2.相关技术描述
用PTH、PTH相关肽和PTH类似物在动物和人体中进行的PTH研究已证明PTH在增加骨形成和骨重吸收方面的有效性，并且激起了对PTH在治疗骨质疏松症和相关骨疾病中的用途的兴趣。然而，高血钙症、高血尿症和肾结石的出现使得PTH的临床应用受到了限制。这些潜在毒副作用的发生和钙代谢的变化一直阻碍着对更高剂量PTH所具有的益处的利用，并且为了安全起见，PTH的血浆浓度必须保持在较窄的范围内。如果能够将主要受破骨细胞介导的高血钙效应和主要受成骨细胞介导的骨形成效应分开，那么就可以增加口服PTH治疗的治疗窗。与PTH相反，降钙素通过直接和破骨细胞相互作用，导致由破骨细胞引起的骨重吸收表面区域的减少和净骨吸收的减少，从而可降低血清钙浓度。由于血浆钙浓度的降低，使尿钙浓度相应地降低，而尿钙浓度降低是已知的肾结石的致病因素。本发明描述了一种口服施用PTH的方法，其拓宽了PTH施用的治疗窗并且允许口服施用更大剂量的PTH并且没有潜在的毒性高血钙副作用。
发明概述
因此，本发明涉及一种口服施用有效剂量的PTH的方法，其包括向需要PTH的患者口服联合施用有效量的PTH和有效量的降钙素。
向灵长类动物施用PTH可导致血清甲状旁腺激素浓度和血清钙浓度增加。相反，向灵长类动物施用鲑鱼降钙素(sCT)可导致血清sCT浓度增加和血清钙浓度降低。现已发现：尽管口服联合施用PTH和降钙素所得到的PTH和降钙素血浆浓度水平和单独施用每种药物时得到的浓度相似，但却非常令人惊讶地导致血清钙浓度降低至单独施用降钙素时所观测到的水平。实际上，降钙素可抵消PTH的高血钙效应并可达到与无PTH存在下单独施用降钙素时相同的血清钙降低效果。将降钙素与PTH治疗一起施用可以获得目前排除使用剂量的PTH所具有的附加疗效，而且没有高血钙副作用。此外，降钙素具有止痛作用，因此可用于抵消通常与施用PTH有关的骨疼痛。
本发明还涉及刺激新骨形成的方法，其包括向需要新骨形成的患者口服施用治疗有效量的PTH和治疗有效量的降钙素。
在另一个实施方案中，本发明涉及治疗或预防骨质疏松症的方法，其包括向需要所述治疗或预防的患者口服施用治疗有效量的PTH和治疗有效量的降钙素。
本发明还涉及适合口服施用的、含有PTH和降钙素的组合物，例如用于同时、并行或依次施用PTH和降钙素的组合物。
本发明还涉及PTH和降钙素在制备用于刺激新骨形成的口服可施用的药物，例如用于同时、并行或依次口服施用PTH和降钙素的药物中的用途。
本发明还涉及用于刺激新骨形成的药物包，其包括适合于口服施用的PTH和降钙素，以及用于其口服施用的使用说明，例如用于同时、并行或依次口服施用PTH和降钙素的药物包。
以下对本发明的详细描述将使本发明的其它特征和优点变得显而易见。
发明详述
甲状旁腺激素或PTH可以是全长的、84个氨基酸形式的甲状旁腺激素，例如人形式的hPTH(1-84)或任何能够模仿hPTH(1-84)的控制钙和磷酸盐代谢以在人体中生成骨的活性的多肽、蛋白质、蛋白质片段或修饰片段，即PTH相关肽和PTH类似物。PTH片段通常包含至少头28个N末端残基且包括PTH(1-28)、PTH(1-31)、PTH(1-34)、PTH(1-37)、PTH(1-38)和PTH(1-41)及其类似物，例如PTS893。PTH可以是单一的PTH或者是两种或多种PTH的任意组合。这些甲状旁腺激素市售可得或可以用本领域成熟的方法、通过重组、通过肽合成或从人体液中提取而得到。
本发明使用的降钙素可以是任何降钙素，包括天然、合成或重组来源的降钙素，以及降钙素衍生物如1，7-Asn-eel降钙素。各种降钙素，包括鲑鱼、猪和鳗鱼降钙素均市售可得且通常被用来治疗例如佩吉特病、恶性高血钙症和骨质疏松症。降钙素可以含有单一的降钙素或两种或多种降钙素的任意组合。优选的降钙素为合成鲑鱼降钙素。
降钙素市售可得或者可通过已知的方法获得。
待施用的PTH的量通常为有效刺激新骨形成的量，即治疗有效的量。该量当然将随着待治疗患者的年龄、体积、性别和状态、待治疗疾病的性质和严重程度等而变化。但是，当预计多次施用组合物时，PTH的量可以低于有效量，即总有效量可以以累积剂量单位的方式施用。当组合物提供缓释的药理学活性剂时，PTH的量也可以高于有效量。待使用的PTH的总量可以通过本领域技术人员已知的方法确定。但是，通常日剂量为约0.001μg/kg至约10mg/kg动物体重、优选1μg/kg至约6μg/kg体重时可以在全身获得满意的结果。
待施用的降钙素的合适剂量当然将随着例如待施用的PTH的量和所治疗病症的严重程度而变化。但是，通常日剂量为约0.5μg/kg至约10μg/kg动物体重、优选1μg/kg至约6μg/kg体重时可以在全身获得满意的结果。
口服施用可以以定期(例如每天或每周一次或多次)、间歇(例如每天或每周内不定期施用)或周期性(例如定期施用一段几天或几周的时间，随后停止施用一段时间)的方式完成。
PTH和降钙素的联合施用包括同时、并行或依次施用这两种化合物。同时施用是指以单一剂量形式施用这两种化合物；并行施用是指在大致相同的时间但却以分开的剂量形式施用这两种化合物；依次施用是指先施用其中一种化合物，然后再施用另一种。依次施用也可以采取这样的形式：同时或并行施用两种化合物，随后停止同时或并行施用，然后继续单独施用两种化合物的其中一种。
根据本发明，口服施用PTH和降钙素可以以任何已知的方式，例如以液体或固体剂量形式完成。
液体剂量形式包括溶液乳剂、混悬剂、糖浆和酏剂。除PTH和/或降钙素外，液体制剂还可以包括本领域常用的惰性赋形剂如，增溶剂如乙醇；油类如棉籽、蓖麻和芝麻油；润湿剂；乳化剂；助悬剂；甜味剂；矫味剂和溶剂如水。
固体剂量形式包括胶囊、软凝胶胶囊、片剂、囊片、粉末剂、颗粒剂或其它固体口服剂量形式，所有这些剂量形式都可以通过本领域熟知的方法制备。除PTH和/或降钙素外，这些固体剂量形式通常还包括用于PTH和/或降钙素的可药用的递送剂。
适宜的递送剂为美国专利5,866,536号所公开的123种修饰氨基酸的任何一种或是美国专利5,773,647号所公开的193种修饰氨基酸的任何一种或它们的任意组合。因此前述美国专利5,773,647号和5,866,536号的内容在此被全部引入作为参考。此外，递送剂可以是任何前述修饰氨基酸的二钠盐以及其乙醇溶剂化物和水合物。适宜的化合物包括以下式I化合物及其水合物和醇溶剂化物，
式I
其中，
R1、R2、R3和R4各自独立地为氢、-OH、-NR6R7、卤素、C1-C4烷基或C1-C4烷氧基；
R5为取代或未取代的C2-C16亚烷基、取代或未取代的C2-C16亚链烯基、取代或未取代的C1-C12烷基(亚芳基)，或取代或未取代的C1-C12芳基(C1-C12亚烷基)；且
R6和R7各自独立地为氢、氧或C1-C4烷基。式I化合物和它们的二钠盐及醇溶剂化物和水合物以及它们的制备方法在WO 00/059863中述及。
优选的递送剂为N-(5-氯水杨酰基)-8-氨基辛酸(5-CNAC)、N-(10-[2-羟基苯甲酰基]氨基)癸酸(SNAD)、N-(8-[2-羟基苯甲酰基]氨基)辛酸(SNAC)以及它们的单钠和二钠盐、其钠盐的乙醇溶剂化物和其钠盐的一水合物及它们的任意组合。最优选的递送剂为5-CNAC的二钠盐及其一水合物。
本发明的药物组合物通常含有递送有效量的一种或多种递送剂，即足以递送获得所需效果的PTH和/或降钙素的量。通常，递送剂的量以重量计为组合物总重的2.5％至99.4％、更优选地为组合物总重的25％至50％。
组合物还可以额外地含有常用量的添加剂，包括但不限于pH调节剂、防腐剂、矫味剂、掩味剂、芳香剂、湿润剂、张力剂、着色剂、表面活性剂、增塑剂、润滑剂如硬脂酸镁、助流剂、压缩助剂、增溶剂、赋形剂、稀释剂如微晶纤维素(例如由FMC公司提供的Avicel PH 102)，或它们的任意组合。其它添加剂可以包括磷酸盐缓冲盐、柠檬酸、乙二醇以及其它分散剂。
组合物还可以包括一种或多种酶抑制剂，如放线酰胺素或表放线酰胺素及其衍生物、抑肽酶(aprotinin、Trasylol)和鲍曼-伯克(Bowman-Birk)抑制剂。
此外，转运抑制剂，即ρ-糖蛋白如Ketoprofin也可以存在于本发明的组合物中。
本发明的固体药物组合物可以通过常规方法制备，例如通过混合一种或几种活性剂、递送剂和任何其它成分的混合物、对其进行捏制并填充至胶囊中，或者不将混合物装入胶囊而对其进行压模、随后进一步压片或压模以得到片剂。此外，可以通过已知的方法制备固体分散体，然后进一步处理以形成片剂或胶囊。
优选地，本发明药物组合物中的成分均匀或均一地混合于固体剂型的任何部分。
本发明的口服施用可以用于需要它的任何动物，包括但不限于哺乳动物，如啮齿类动物、牛、猪、狗、猫和灵长类动物，特别是人。
以下实施例进一步阐明了本发明。
实施例1
按下述方式制备了以下胶囊：
由400mg 5-CNAC二钠盐/800mcg sCT/800mcg PTH制备的胶囊(胶囊1A)
由400mg 5-CNAC二钠盐/800mcg PTH制备的胶囊(胶囊1B)
由400mg 5-CNAC二钠盐/800mcg sCT制备的胶囊(胶囊1C)
由800mcg PTH制备的胶囊(胶囊1D)
所述PTH为PTH片段1-34，市售可得；sCT为鲑鱼降钙素。所述胶囊均被制成干燥混合物，其是通过称量出每种组分，将它们混合在一起得到均匀混合物，然后手工将400mg混合物填充至每个胶囊中而制得。对于仅含有PTH的胶囊，称出400mg PTH后直接将其置于每个胶囊中。
实施例2
在灵长类动物中的施用
按如下方法将实施例1制备的胶囊施用于恒河猴(Rhesus monkey)：每组四只猴子，对每只猴子给予1粒实施例1制备的胶囊，方法如下：
给药前将恒河猴禁食过夜并在研究期间将其束缚于椅子中，使其保持完全清醒。通过强饲管施用胶囊，随后给予10mL水。
于给药后0、0.25、0.5、0.75、1、1.5、2、3、4、5和6小时收集血样。用放射免疫分析法测定血浆鲑鱼降钙素和血浆PTH。将得自每组猴子的灵长类血浆鲑鱼降钙素(sCT)和PTH的结果平均，计算最大平均血浆降钙素并报道于表1-5。
表1
| 鲑鱼降钙素和PTH对恒河猴进行口服施用后sCT的血浆浓度(pg/mL)剂量：1粒胶囊1A | |||||||||||
| 动物编号 | 时间[小时] | ||||||||||
| 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 | |
| S961 | 0 | 27 | 39 | 54 | 49 | 39 | 26 | 12 | 0 | 0 | 0 |
| S983 | 0 | 386 | 747 | 628 | 774 | 802 | 811 | 305 | 174 | 36 | 0 |
| S985 | 0 | 470 | 502 | 603 | 648 | 634 | 521 | 204 | 73 | 40 | 32 |
| E56 | 0 | 251 | 270 | 273 | 246 | 171 | 124 | 49 | 19 | 0 | 11 |
| 平均值 | 0 | 284 | 389 | 389 | 429 | 411 | 370 | 143 | 66 | 19 | 11 |
| SD | 0 | 194 | 304 | 276 | 339 | 365 | 364 | 137 | 78 | 22 | 15 |
| SEM | 0 | 97 | 152 | 138 | 170 | 182 | 182 | 68 | 39 | 11 | 8 |
| LLOQ＝11pg/mL，低于LLOQ的浓度设定为0。 | |||||||||||
表2
| 鲑鱼降钙素和PTH对恒河猴进行口服施用后PTH的血浆浓度(pg/mL)剂量：1粒胶囊1A | |||||||||||
| 动物编号 | 时间[小时] | ||||||||||
| 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 | |
| S961 | 0 | 0 | 0 | 26 | 27 | 28 | 0 | 0 | 0 | 0 | 0 |
| S983 | 0 | 175 | 309 | 181 | 202 | 226 | 213 | 75 | 34 | 0 | 0 |
| S985 | 0 | 133 | 206 | 261 | 299 | 252 | 175 | 75 | 29 | 0 | 0 |
| E56 | 0 | 89 | 124 | 158 | 144 | 105 | 90 | 61 | 35 | 28 | 0 |
| 平均值 | 0 | 99 | 160 | 156 | 168 | 153 | 119 | 53 | 25 | 7 | 0 |
| SD | 0 | 75 | 131 | 98 | 113 | 105 | 95 | 36 | 17 | 14 | 0 |
| SEM | 0 | 37 | 65 | 49 | 57 | 52 | 47 | 18 | 8 | 7 | 0 |
| LLOQ＝25pg/mL，低于LLOQ的浓度设定为0。 | |||||||||||
表3
| 鲑鱼降钙素对恒河猴进行口服施用后的血浆钙浓度(pg/mL)剂量：1粒胶囊1C | |
| 动物编号 | 时间[小时]0 1 2 3 4 5 6 |
| R944S966S945S961CP943S9510 | 0.00 -3.08 -6.54 -8.99 -13.89 -12.88 -13.750.00 -9.74 -17.30 -23.43 -24.86 -31.27 -30.700.00 -2.36 -2.81 -7.24 -9.75 -11.23 -11.960.00 -7.00 -12.92 -13.06 -18.69 -18.27 -23.910.00 -1.54 -7.97 -10.36 -17.23 -13.50 -12.600.00 -9.16 -12.05 -15.07 -20.16 -22.49 -26.07 |
| 平均值SDSEM | 0.00 -5.48 -9.93 -13.02 -17.43 -18.27 -19.830.00 3.61 5.17 5.82 5.21 7.59 8.060.00 1.47 2.11 2.38 2.13 3.10 3.29 |
表4
| PTH对恒河猴进行口服施用后PTH的血浆浓度(pg/mL)剂量：1粒胶囊1B | |||||||||||
| 动物编号 | 时间[小时] | ||||||||||
| 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 | |
| R944 | 0 | 83 | 191 | 300 | 360 | 262 | 154 | 35 | 0 | 0 | 0 |
| S963 | 0 | 127 | 332 | 663 | 1258 | 150 | 34 | 0 | 0 | 0 | 0 |
| 平均值 | 0 | 105 | 262 | 482 | 809 | 206 | 94 | 17 | 0 | 0 | 0 |
| SD | 0 | 31 | 100 | 257 | 635 | 79 | 85 | 25 | 0 | 0 | 0 |
| SEM | 0 | 22 | 71 | 182 | 449 | 56 | 60 | 17 | 0 | 0 | 0 |
表5
| PTH对恒河猴进行口服施用后PTH的血浆浓度(pg/mL)剂量：1粒胶囊1D | |||||||||||
| 动物编号 | 时间[小时] | ||||||||||
| 0 | 0.25 | 0.50 | 0.75 | 1 | 1.5 | 2 | 3 | 4 | 5 | 6 | |
| R927 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| S982 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 平均值 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| SD | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| SEM | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| LLOQ＝25pg/mL，低于LLOQ的浓度设定为0。 | |||||||||||
从表1-5中的数据可以看出：无论所述化合物是分别施用还是一起施用，sCT和PTH的血浆水平基本上是相同的。但是，尽管口服联合施用PTH和降钙素得到的PTH和降钙素血浆浓度水平与单独施用每种药物时得到的浓度相似，但却非常令人惊讶地导致血清钙浓度降低至单独施用降钙素时的水平。
前述的实施方案和实施例仅仅用来阐明本发明而不是对本发明进行限定。各种其它实施方案和改变均处于本发明的范围之内且易于被本领域技术人员理解。
Claims (13)
1.口服施用有效剂量的PTH的方法，其包括向需要PTH的患者口服施用有效量的PTH和有效量的降钙素。
2.权利要求1的方法，其中的降钙素为鲑鱼降钙素。
3.刺激新骨形成的方法，其包括向需要新骨形成的患者口服施用治疗有效量的PTH和治疗有效量的降钙素。
4.权利要求3的方法，其中的降钙素为鲑鱼降钙素。
5.治疗或预防骨质疏松症的方法，其包括向需要所述治疗或预防的患者口服施用治疗有效量的PTH和治疗有效量的降钙素。
6.权利要求5的方法，其中所述降钙素为鲑鱼降钙素。
7.用于口服施用的组合物，其含有PTH和降钙素。
8.权利要求7的组合物，其中的PTH为人形式的PTH。
9.权利要求8的组合物，其中的降钙素为鲑鱼降钙素。
10.PTH和降钙素在制备用于刺激骨形成的口服可施用的药物中的用途。
11.权利要求10的用途，其中的PTH为人形式的PTH。
12.权利要求11的用途，其中的降钙素为鲑鱼降钙素。
13.用于刺激新骨形成的药物包，其包括适于口服施用的PTH和降钙素以及用于其口服施用的使用说明。
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| CN104800564A (zh) * | 2015-04-02 | 2015-07-29 | 中国人民解放军济南军区总医院 | 一种治疗血虚不荣型甲状旁腺功能减退症的中药组合物 |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE356631T1 (de) | 2001-06-01 | 2007-04-15 | Novartis Pharma Gmbh | Orale verabreichung von parathyroidhormon und calcitonin |
| IL159714A0 (en) * | 2001-08-17 | 2004-06-20 | Novartis Ag | 5-cnac as oral delivery agent for parathyroid hormone fragments |
| US20050054557A1 (en) * | 2002-05-09 | 2005-03-10 | Goldberg Michael M. | Compositions for delivering parathyroid hormone and calcitonin |
| RU2507196C2 (ru) | 2005-09-19 | 2014-02-20 | Эмисфире Текнолоджис, Инк. | Кристаллические формы динатриевой соли n-(5-хлорсалицилоил)-8-аминокаприловой кислоты |
| GB0522566D0 (en) * | 2005-11-04 | 2005-12-14 | Novartis Ag | Organic compounds |
| EP1945245A2 (en) * | 2005-11-10 | 2008-07-23 | The Board of Control of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
| CA2626933C (en) * | 2005-11-17 | 2015-12-29 | Novartis Ag | Pharmaceutical composition |
| RU2469728C2 (ru) | 2007-11-02 | 2012-12-20 | Эмисфире Текнолоджис, Инк. | Способ лечения дефицита витамина b12 |
| RU2494755C2 (ru) | 2008-08-18 | 2013-10-10 | Интера Био Лтд. | Способы и композиции для перорального введения белков |
| CN104857505A (zh) * | 2008-08-18 | 2015-08-26 | 安特拉贝欧有限公司 | 用于口服给予蛋白质的方法和组合物 |
| BR112012013725A2 (pt) | 2009-12-07 | 2017-01-10 | Univ Michigan Tech | paratormônio de urso preto e métodos de usar o paratormônio de uso preto. |
| WO2012130193A1 (en) | 2011-03-31 | 2012-10-04 | Zentiva, K.S. | Non-covalent soluble complexes of teriparatide with polysaccharides and a dosage form of teriparatide for oral administration |
| KR101796604B1 (ko) * | 2016-08-30 | 2017-11-10 | 목포대학교 산학협력단 | 위장관 흡수증진제를 함유하는 부갑상선 호르몬의 경구 투여 제형 |
| WO2019098811A2 (ko) | 2017-11-20 | 2019-05-23 | 주식회사 노브메타파마 | Chp(시클로-히스프로)를 포함하는 골 손실 질환의 예방, 개선 또는 치료용 조성물 |
| KR102115353B1 (ko) * | 2019-05-17 | 2020-05-26 | 주식회사 노브메타파마 | Chp(사이클로-히스프로) 및 부갑상선 호르몬을 포함하는 골 손실 질환의 예방, 개선 또는 치료용 조성물 |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4692433A (en) * | 1983-10-12 | 1987-09-08 | The Regents Of The University Of California | Method and composition for regulating serum calcium levels of mammals |
| US5364840A (en) * | 1989-12-05 | 1994-11-15 | Vical, Inc. | Synthetic calcitonin peptides |
| US5118667A (en) * | 1991-05-03 | 1992-06-02 | Celtrix Pharmaceuticals, Inc. | Bone growth factors and inhibitors of bone resorption for promoting bone formation |
| WO1994018955A1 (en) * | 1993-02-22 | 1994-09-01 | Alza Corporation | Compositions for oral delivery of active agents |
| US5866536A (en) * | 1995-03-31 | 1999-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US5650386A (en) | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
| US5723577A (en) | 1995-07-13 | 1998-03-03 | Biomeasure Inc. | Analogs of parathyroid hormone |
| US5955574A (en) * | 1995-07-13 | 1999-09-21 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Analogs of parathyroid hormone |
| ES2263428T3 (es) | 1997-02-07 | 2006-12-16 | Emisphere Technologies, Inc. | Compuesto y composicion para agentes activos de administracion. |
| SE9702401D0 (sv) | 1997-06-19 | 1997-06-19 | Astra Ab | Pharmaceutical use |
| DE19915272A1 (de) * | 1999-04-03 | 2000-10-05 | Vetter & Co Apotheker | Spritze für medizinische Zwecke |
| JP4588221B2 (ja) * | 1999-04-05 | 2010-11-24 | エミスフェアー・テクノロジーズ・インク | 活性剤を送達するための二ナトリウム塩、一水和物、およびエタノール溶媒和物 |
| WO2001032201A2 (en) | 1999-10-29 | 2001-05-10 | Eli Lilly And Company | A pharmaceutical composition having high cell membrane permeability |
| US7049283B2 (en) * | 2000-12-06 | 2006-05-23 | Novartis Ag | Pharmaceutical compositions for the oral delivery of pharmacologically active agents |
| ATE356631T1 (de) | 2001-06-01 | 2007-04-15 | Novartis Pharma Gmbh | Orale verabreichung von parathyroidhormon und calcitonin |
| IL159714A0 (en) * | 2001-08-17 | 2004-06-20 | Novartis Ag | 5-cnac as oral delivery agent for parathyroid hormone fragments |
| US7318925B2 (en) * | 2003-08-08 | 2008-01-15 | Amgen Fremont, Inc. | Methods of use for antibodies against parathyroid hormone |
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